Delivering drugs to the lymphatic system has been realized as an essential mechanism for the treatment of numerous diseases. However, the physiology and hydrostatics of the lymphatics has made current methodologies ineffective for targeting and directly delivering drugs to the lymphatic system. Many currently utilized methods first target the blood system, which at low rates, move out of the blood capillaries, into the interstitial tissues, and into the lymphatic system. These approaches rely on specific drug chemical modifications or drug lipid or nano carriers.
The lymphatic system is one of the principle components of the immune system. It has an important role in transporting immugens, pathogens, body fluids and particulate materials including proteins and fat particles from the interstitial tissues. The lymphatics have also long been appreciated as having an important role in immunity and in numerous disease conditions. The lymphatics are a primary route for both the occurrence of certain cancers and the metastatic dissemination of primary tumors. For example, it is estimated that lymphomas (e.g., Hodgkin lymphoma and BIT cell neoplasms) account for at least 5% of all cancer occurrences and over half of all blood cancers. Additionally, the most common route for metastasis is from malignant cells from a primary tumor entering the lymphatic system and seeding secondary tumors at distant locations and other organ tissues. In non-small cell lung cancer (NSCLC) survival following surgery falls by about half if a tumor is found in the lymph nodes within the lung, and by another half if lymph nodes just outside of the lung (mediastinum) are involved.
The lymphatics are also known to play important roles during episodes of inflammation stemming from infection and chronic disease. During infection, there is a physiological need for interstitial fluid drainage to remove and filter out harmful microbes, damaged cells, and toxic byproducts. In response, the local lymphatics undergo a robust inflammation induced lymphangiogenesis (i.e., lymphatic capillary growth and expansion). Often the presence of an inflammatory condition results in lymph node swelling or lymphadenitis. Furthermore, physiological responses of lymphangiogenesis and lymphadenitis are known to be important in several classes of chronic diseases including rheumatoid arthritis, diabetes, inflammatory bowel disease, and chronic transplantation rejection.
Non-targeted attempts at delivery to the lymphatic vasculature have included different parenteral administration methods, intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), or intradermal (i.d.) injections or oral delivery methods. Each of these methods has been met with variable levels of lymphatic absorption likely depending on the injection site, physiology of the test animal, and overall physiology of the lymphatics, which have highly variable absorption kinetics. Orally or intravenously delivered drugs first enter the blood system, which results in systemic distribution to different organs, and orally delivered drugs often suffer from first pass metabolism effects. Other parenteral administration methods (s.c., i.m., and i.d.) for lymphatic delivery have been inconsistent and not reproducible. One such study found that high levels of recombinant interferon α-2a was located within the lymph following either s.c. or i.d. injection of sheep cannulated legs, see, Supersaxo, A. et al., Pharm. Res., 5 (8), 472-476 (1988). However, these results were not able to be duplicated in other studies using rabbits following s.c. administration (see, Yoshikawa, H. et al., J Pharmacobio-Dyn., 8 (3), 206-210 (1985).
Various second generation targeted delivery attempts have been made to use carrier based systems to target the lymphatics, which include trans-lymphatic drug delivery systems (e.g., liposomes and lipid-based nano formulations), micro or nanoparticle carriers, macromolecule polymers, polymer micelles, activated carbons, silicon, and O/W or W/O nano-emulsions and anti-body based lymphatic targeting, see, for example, Xie et al., Expert Opin. Drug Deliv., 6 (8), 25 785-792 (2009) and Zhang and Wei-Yue., Cancer Biol Med., (11), 247-254 (2014).
Typically, these carrier systems are injected into the body via traditional i.v., s.c., i.d., or i.m. routes or taken orally. As discussed above, i.v. and oral routes of administration result in poor lymphatic uptake because these administered carriers may be diluted systemically and also must first leave the blood system to enter into the lymphatics. Known problems associated with liposomes and nano particle formulations include low lymphatic uptake rates and unpredictable drug release rates, which require highly specific liposomal formulations to be developed for each drug to be delivered. In addition, injected liposome carriers often become stuck within the interstitial tissues unable to enter the lymphatic system, requiring a secondary mechanism of macrophage mediated transport see, Oussoren et al., Adv. Drug Deliv. Rev., 50 (1-2), 143-156 (2001).
Other approaches describing implantable devices for releasing drugs locally to the lymphatics are described in WO 2007/047539 and US 2010/0278725. However, these implantable devices for lymphatic delivery are costly and invasive, which can lead to increased patient pain and reduced compliance and satisfaction. Furthermore, these approaches rely on the placement of such devices within the subcutaneous layers of the skin, which have little or no blood or lymphatic vasculature. Approaches for delivery to the lymphatics using intradermal injections have been described in US 20050180952. Techniques such as these utilize area concentrated bolus injections, which can lead to uncontrolled drug absorption rates depending on the area of injection and waste of expensive drug materials. In addition, injecting a drug at a single administration depth in the dermis can lead to patient to patient variability due to the drug being delivered in a location with reduced lymphatic capillaries or diffusion or movement of the drug deeper into the subcutaneous tissue. Other common intradermal injection techniques such as the Mantoux tuberculin skin test are known to be imprecise and difficult to administer reproducibly.
Thus, there is a need for new, reproducible, and efficient methods for delivering agents (e.g., bioactive agents) to the lymphatic system.